Pharmaceutical compositions for direct systemic introduction

ABSTRACT

The invention relates to pharmaceutical compositions for direct systemic introduction, are also known as DSI pharmaceutical compositions, for used as human veterinary pharmaceutical compositions. In one embodiment, the invention relates to a pharmaceutical composition for direct system introduction comprising bovine gelatin, mannitol, an optional surfactant, an optional flavorant, and an active pharmaceutical ingredient. A DSI pharmaceutical composition of the invention has a disintegration time of 7 seconds or less in deionized water maintained at 37.0° C.±0.5° C. The invention also relates to a method of delivering an active pharmaceutical ingredient to an animal comprising the step of placing a DSI pharmaceutical composition of the invention into a mucosal cavity of an animal to be treated with the active pharmaceutical ingredient and to the corresponding methods of treatment.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.14/398,085, filed Oct. 30, 2014; which claims priority to PCTInternational Application No. PCT/US2012/070031, filed Dec. 17, 2012;which claims priority to U.S. Provisional Application No. 61/641,509,filed May 2, 2012; U.S. Provisional Application No. 61/674,435, filedJul. 23, 2012; and U.S. Provisional Application No. 61/678,355, filedAug. 1, 2012; the disclosures of which are incorporated herein byreference.

BACKGROUND

The delivery of therapeutic agents for animals, for example humans,equines, bovines, canines, felines, ovines, and porcines suffer fromnumerous serious disadvantages for a variety of reasons. Injectableformulations, which typically provide rapid onset of activity, are mostpreferably administered in an environment of cleanliness to preventinfections entering the injection site. But, this is difficult to ensureoutside of a clinical setting. And cleanliness is nearly impossible toensure in a typical horse barn, farm, field or racetrack. Along withthis rapid onset of activity, an injectable therapeutic typicallysuffers from a relatively short and single-peaked Time versus BloodConcentration profile.

Conventional oral dosing of animals also suffers from a variety ofdisadvantages. For example, the animal can spit out the formulation,resulting in a loss of the full dosage. Also, if administered byintubation, the bioavailability can vary considerably due to theinherent and unique characteristics of each animal's digestive system,i.e., the amount of food in the animal's stomach, the length of timesince its last feeding, and the animal's levels of digestive enzymes,which may vary due to other environmental conditions, etc. Also, theactive ingredient in the oral formulation is sometimes unstable. In somecases the active ingredient in an oral formulation may be unstablebecause of the pH and/or digestive materials present in an animal'sstomach. Moreover, administering conventional oral dosages forms to ananimal, e.g., a horse, creates the risk of inadvertently dosing thehuman administrator with the drug substance.

Another disadvantage of many oral and injectable formulations is thatthose formulations require administering a relatively high masspercentage (“mass %”) of inactive material to the animal. For example,many oral and injectable formulations comprise significant amounts ofcarriers and/or excipients that provide no direct benefit to the animal.Many care providers generally agree that animals should not consumeunnecessary pharmaceutical substances. Accordingly, it would beadvantageous to minimize the amount of non-therapeutic materialsadministered to an animal when providing the pharmaceutically activesubstance. For example, when providing omeprazole to an animal in needthereof, many conventional formulations comprise more than 50% of aninactive substance having no therapeutic effect. Conventional oralformulations of omeprazole may also often suffer from thedisadvantageous correlation between bioavailability and the contents ofthe animal's stomach. For example, bioavailability may be lessened onaccount of the animal having food present in its stomach.

Fast release pharmaceutical formulations have been disclosed in the art.These may include multi-particulate fast disintegrating tablets asdisclosed, for instance in U.S. Pat. No. 6,596,311; the so-calledrapidly dispersing “3-D platform”, disclosed in U.S. Pat. No. 6,471,992;and pectin-based dissolvable films, such as disclosed in US2007/0042023.Immediate release compositions are disclosed WO 2012/106058. Each ofthese disclosures is incorporated herein by reference.

Still, there exists a need in the art to provide improved therapeuticmethods for animals (for example humans, equines, bovines, ovines,canines, felines and porcines) which obviate many of the disadvantagesand side effects of the commonly used injectable and oral formulations.

There is also a need in the art to provide methods for the treatment ofhumans, equines, bovines, canines, felines, ovines, and porcines equineswith drug products which give an earlier onset of action, reduce thenumber and severity of side effects, lessen the risk of infection atinjection sites, and mitigate the bioavailability issues incident toadministering the drug via absorption within the digestive tract of theanimal.

There is a still another need in the art to provide methods which enabletreatment of the animal patient that provide more reliable andpredictable clearance from the animal.

The invention disclosed here answers one or more of these needsdiscussed above. The features, objects, and advantages of the disclosedinvention will be apparent to those skilled in the art from thedescription of the invention, and from the claims.

SUMMARY OF THE INVENTION

The invention relates to pharmaceutical compositions for direct systemicintroduction (DSI), which are also known as DSI pharmaceuticalcompositions. DSI pharmaceutical compositions may used in both as humanpharmaceutical compositions and veterinary pharmaceutical compositions.Various DSI pharmaceutical compositions are described herein.

In one embodiment, the invention relates to a pharmaceutical compositionfor direct system introduction comprising: about 5-20 mass % bovinegelatin, about 5-20 mass % mannitol, about 0-1 mass % of a surfactant,about 0-0.5 mass % of a flavorant, and about 60-90 mass % of an activepharmaceutical ingredient. The pharmaceutical composition may compriseabout 10-17 mass % bovine gelatin, about 10-17 mass % mannitol, andabout 0-0.5 mass percent of a surfactant. Alternatively, thepharmaceutical composition may comprise about 10-13 mass % bovinegelatin, about 12-15 mass % mannitol, and about 0.1-0.3 mass % of asurfactant. Omeprazole is one active pharmaceutical ingredient that maybe formulation in a pharmaceutical composition of the invention.

Another embodiment of the invention relates to a DSI pharmaceuticalcomposition, such as described herein, having a disintegration time of 5seconds or less in deionized water maintained at 37.0° C.±0.5° C. A DSIpharmaceutical composition of the invention may have a disintegrationtime of 3 seconds or less in deionized water maintained at 37.0° C.±0.5°C.

The invention also relates to a method of delivering an activepharmaceutical ingredient to an animal comprising the step of placing aDSI pharmaceutical composition of the invention into a mucosal cavity ofan animal to be treated with the active pharmaceutical ingredient. Theinvention also relates to various methods of treatment administering anactive pharmaceutical ingredient in this manner.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the DOE Response surface of Factors 1 & 2 (Factor 3 fixedat I5° C. shelf temperature) as described in Example 3.

FIG. 2 depicts the DOE Response surface of Factors 1 & 2 (Factor 3 fixedat 0° C. shelf temperature) as described in Example 3.

FIG. 3 depicts the DOE Response surface of Factors 1 & 2 (Factor 3 fixedat −15° C. shelf temperature) as described in Example 3.

DETAILED DESCRIPTION

Disclosed herein are pharmaceutical compositions and methods fortreating animals, for example humans, equines, bovines, canines,felines, ovines, and porcines. Various embodiments compriseadministering an active pharmaceutical ingredient, also known as atherapeutic agent, into the bloodstream of the animal by introducing ittransdermally across the animal's non-keratinous fibers, e.g., via theoral cavity, anal cavity, vaginal cavity, nasal cavity, gingival mucosa,lingual mucosa, palatal mucosa, pharyngeal mucosa, sublingual mucosa,and/or non-gastric mucosa. In various embodiments, a majority of theformulation may be absorbed prior to reaching the gastric mucosa. Incertain embodiments, the formulation may be adapted for animals, forexample humans, equines, bovines, canines, felines, ovines, and porcinesto dissolve in a relatively short period of time, e.g., 90 seconds orless.

In some embodiments, administering a DSI pharmaceutical composition ofthe invention provides for faster onset of the therapy, diminishedoccurrences of the side-effects due to nonuniformity of bioavailabilityof the active pharmaceutical ingredient, and/or more accurate dosing. Inat least some embodiments, these features result in dose lowering.Further, in at least some embodiments, such administration may result ina greater portion of the therapeutic agent actually being directlyintroduced systemically into the circulatory system for its therapeuticeffect. For example, in the case of omeprazole, the DSI pharmaceuticalcompositions disclosed herein provide an advantage because thebioavailability of omeprazole is not limited by the presence of matter(e.g., food) in the animal's stomach. For example, the disclosed methodsof administering the active pharmaceutical ingredient omeprazole do notrequire fasting the animals prior to administering omeprazole. And thebioavailability of omeprazole is not compromised by the contents of theanimal's stomach.

Also disclosed herein are methods for the treatment and control ofvarious diseases afflicting animals, for example equines, bovines,canines, felines, ovines, and porcines, with improved safety for theboth the animal and the person administering the therapeutic agent. Inat least certain exemplary embodiments, the compositions and methods areuseful for administration to humans. For example, disclosed herein aremethods of treating gastroesophageal reflux disease, gastritis, pepticulcer disease, dyspepsia, laryngopharyngeal reflux, Zollinger-Ellisonsyndrome, duodenal ulcers and/or preventing gastric ulcers (e.g.,gastric ulcers associated with NSAID therapy or Chrohn's disease) and/orcontrolling the production of digestive fluids (e.g., gastric acids)and/or normalizing the pH of an animal's stomach comprisingadministering a DSI compound comprising one or more proton pumpinhibitors (e.g., omeprazole and/or any of its stereoisomers).

Administering therapeutic agents to the animal without needles, via thenon-keratinous tissues into a mucosal cavity, e.g., the oral cavity,anal cavity, vaginal cavity, nasal cavity, gingival mucosa, lingualmucosa, palatal mucosa, pharyngeal mucosa, sublingual mucosa, and/ornon-gastric mucosa results in rapid onset of activity, more accuratedosing, lowered dosing, an absence or diminishment of side-effects, andgreater safety to both the animal and the administrator of theformulation. In some cases the therapeutic agents may be administeredvia the animal's oral cavity, anal cavity, vaginal cavity, nasal cavity,gingival mucosa, lingual mucosa, palatal mucosa, pharyngeal mucosa,sublingual mucosa, and/or non-gastric mucosa.

As used herein, the term “oral cavity” means that portion of thealimentary canal from the orifice conventionally referred to as themouth, including, for example the area distally from the mouth to theesophagus and all tissues including, for example under the tongue(sublingual), on the top of the tongue, and/or between the cheek andgums (buccal), the mucal membranes, epithelium, and gums.

As used herein, the term “non-gastric mucosa” refers to the pre-gastricmucosal cells, e.g., oral mucosa, including the mucous membrane beneaththe tongue, and/or the buccal mucosa at the inside of the cheek and gumand absorption sites in the esopaghus.

As used herein, the term “pre-gastric” refers to all parts of thealimentary canal beginning at the mouth and continuing to the juncturewith the first secretory stomach.

As used herein, “Direct Systemic Introduction” (“DSI”), meansadministering one or more therapeutically active agent directly to thecirculatory system of an animal via a formulation administered andabsorbed across non-keratinous fibers, e.g., the oral cavity and/or thenon-gastric mucosa. DSI may, in at least some embodiments, providerelatively high systemic concentrations of the active agents, e.g. byallowing agents to pass directly into the systemic circulation avoidingthe destructive activities in the digestive tract by gastric breakdown,metabolism in the wall of the GI tract and first pass metabolism by theliver. In one embodiment, administering a DSI pharmaceutical compositioncomprises contacting the animal's first secretory stomach with less thanabout 50% of the DSI pharmaceutical composition administered to theanimal.

DSI may result in higher systemic availability of therapeutic agents inthe animal for their desired therapeutic effects vis-à-vis productsformulated in conventional oral delivery systems. DSI providesadvantages over traditional oral, intravenous, intramuscular, andsubcutaneous routes of administration, in that more of the drug may beavailable systemically for its desired therapeutic effects. For example,in equines, DSI can provide more rapid metabolic clearance of the drug,resulting in a shortened withdrawal time to clear the animal forperformance racing. See, e.g., “Equine Drug Testing and TherapeuticMedication Regulation: 2009 Policy of the National Horsemen's Benevolentand Protective Association, Inc.” edited by Thomas Tobin & Kent H.Stirling, which discusses the necessary withdrawal times for performanceanimals.

A DSI pharmaceutical composition of the invention disintegrates quicklyin water. A DSI pharmaceutical composition of the invention generallyhas a disintegration time of 7 seconds or less in deionized watermaintained at 37.0° C.±0.5° C. A DSI pharmaceutical composition of theinvention may have a disintegration time of 4 seconds or less indeionized water maintained at 37.0° C.±0.5° C.

The raid dissolution of the DSI pharmaceutical compositions disclosedherein allows them to also dissolve rapidly when in contact with ananimal's non-keratinous fibers/mucosal cavity, for example, the oralcavity and/or the non-gastric mucosa. In some embodiments, theformulations contemplated herein will dissolve when in contact with theanimal's non-keratinous fibers, e.g., the oral cavity and/or thenon-gastric mucosa in about 90 seconds or less. In some embodiments, theDSI pharmaceutical composition will dissolve in about 75 seconds orless, such as in about 60 seconds or less, about 45 seconds or less,about 30 seconds or less, about 20 seconds or less, about 10 seconds orless or about 5 seconds or less. In some embodiments, the DSIpharmaceutical composition dissolves in less than about 3 seconds.

A further benefit of the DSI dosing of an animal is that the personadministering may be able to more quickly titrate an appropriate dosagefor the level and severity of the condition of the animal. Using typicalroutes of administration, due to metabolic disposition and the overallhealth of the animal, it may take a practitioner a period of severaldays to achieve an appropriate dose to treat and control a condition.One advantage of a DSI pharmaceutical composition is that thepractitioner may reliably assume therapeutic effects within a shortperiod of time, and adjust the level of administration of the drug, asneeded.

In at least some embodiments, DSI pharmaceutical compositions permit ashorter withdrawal time from treatment than with some conventional oraldosing regimens. By way of example only, typically, an equine patientwill need to be withdrawn from many medications for periods ranging from24-72 hours prior to performance racing. This results in interruption ofthe therapy, and can lead to a worsening of the existing disease, or atthe least, a slower recovery than if the withdrawal had not occurred. Inmany cases using DSI therapy, however, the equine patient may only needto discontinue the therapy for a period as short as 0-12 hours or not atall, depending upon the particular therapeutic agent being utilized inthe methods of the present disclosure.

In at least one exemplary embodiment, the methods herein areadministered to the circulatory system of the animal via a DSIpharmaceutical composition administered and absorbed via thenon-keratinous fibers/mucosal cavity, such as in the oral cavity and/orthe non-gastric mucosa, adapted for humans, equines, bovines, canines,felines, ovines, and porcines, resulting in rapid absorption of theactive ingredient and faster clearance. Due to both administration andabsorption to the oral cavity and/or the non-gastric mucosa, theresultant effect is DSI.

In some embodiments, the oral dissolution of the disclosed DSIpharmaceutical compositions occurs without the addition ofnon-biological liquids or accelerants. For example, the DSIpharmaceutical compositions may disintegrate rapidly upon contact withthe animal's biological fibers and/or biological fluids. In someembodiments, the DSI pharmaceutical compositions may be administeredwithout the need for any additional sources of accelerant, dissolvingagent, or contemporaneous drink.

In one embodiment, the DSI pharmaceutical composition comprises a protonpump inhibitor as the active pharmaceutical ingredient. As used in thisapplication, the term “proton-pump inhibitor” (sometimes abbreviated“PPI”) refers to a group of drugs that provide pronounced andlong-lasting reduction of gastric acid production. Without being boundby any theory, proton pump inhibitors are believed to act byirreversibly blocking the hydrogen/potassium adenosine triphosphataseenzyme system (often described in terms of “the H+/K+ ATPase” or“gastric proton pump”) of the gastric parietal cells. As used in thisapplication, the term proton pump inhibitor includes but is not limitedto omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole,esomeprazole, etc.

In one embodiment, the DSI pharmaceutical composition comprisesomeprazole. In one embodiment, the DSI pharmaceutical compositioncomprises micronized omeprazole. As used herein, the term “micronized”means having an average particle diameter of between about 1×10⁻³ toabout 1×10⁻⁷ meters. For example, in some embodiments the disclosed DSIpharmaceutical compositions comprising omeprazole are formulated withmicronized omeprazole having an average particle diameter of about 1 toabout 10 microns.

In one embodiment, the DSI pharmaceutical composition comprises both aproton pump inhibitor and an H2 blocker (also known as an H2 receptorantagonist). In one embodiment, the DSI pharmaceutical compositioncomprises omeprazole and at least one compound chosen from famotidine,cimetidine, ranitidine, and nizatidine.

One embodiment of the invention provides DSI pharmaceutical compositionscomprising greater than about 50 mass % of an active pharmaceuticalingredient, such as omeprazole. In one embodiment, the DSIpharmaceutical composition comprises greater than about 60 mass % ofomeprazole as an active pharmaceutical ingredient. In anotherembodiment, the DSI pharmaceutical composition comprises greater thanabout 70 mass % of an active pharmaceutical ingredient. In otherembodiments, the DSI pharmaceutical composition comprises about 70-90mass % of an active pharmaceutical ingredient or about 75-85 mass % ofan active pharmaceutical ingredient.

For example, a DSI pharmaceutical composition o according to theinvention may contain about 5-25 mass % bovine gelatin, 5-25 mass %mannitol, about 0-1 mass % of a surfactant, about 0-0.5 mass % of aflavorant and about 50-90 mass % of an active pharmaceutical ingredient.A preferred DSI formulation contains about 5-20 or 10-15 mass % bovinegelatin, about 5-20 or 10-15 mass % mannitol, about 0-0.7 mass % of asurfactant, about 0.001-0.4 mass % of a flavorant and about 65-85 mass %of anomeprazole. Also disclosed herein are products produced by theabove-described methods. In one embodiment the product producedcomprises about 70 mass % omeprazole. In one embodiment, a DSIpharmaceutical composition of omeprazole according to the invention maycontain about 5-25 mass % bovine gelatin, 5-25 mass % mannitol, about0-2 mass % of a surfactant, about 0-1 mass % of a flavorant and about60-90 mass % of omeprazole. A preferred DSI formulation contains about10-15 mass % bovine gelatin, 10-15 mass % mannitol, about 0.001-0.7 mass% of a surfactant, about 0.001-0.4 mass % of a flavorant and about 65-85mass % of omeprazole. Also disclosed herein are products produced by theabove-described methods. In one embodiment the product producedcomprises about 70 mass % omeprazole.

In at least one embodiment, the methods of treatment described hereincomprise administering the active ingredient (e.g., omeprazole) in adehydrated form, such that the active ingredient is rapidly andefficiently delivered to the animal's circulatory system upon contactwith the animal's natural biological fluids.

In one embodiment, the DSI pharmaceutical composition provides a Tmax ofless than about 200 minutes. In another embodiment, the DSIpharmaceutical composition provides a Tmax of less than about 150minutes. In another embodiment, the DSI pharmaceutical compositionprovides a Tmax of less than about 120 minutes. In another embodiment,the DSI pharmaceutical composition provides a Tmax of less than about100 minutes. In another embodiment, the DSI pharmaceutical compositionprovides a Tmax of less than about 80 minutes. In another embodiment,the DSI pharmaceutical composition provides a Tmax of less than about 60minutes. In another embodiment, the DSI pharmaceutical compositionprovides a Tmax of less than about 50 minutes. In another embodiment,the DSI pharmaceutical composition provides a Tmax of less than about 40minutes. In another embodiment, the DSI pharmaceutical compositionprovides a Tmax of less than about 30 minutes.

In one embodiment, administering a DSI pharmaceutical composition asdisclosed hereing provides a first Tmax and a second Tmax. As usedherein the term “first Tmax” refers to the first relative maximum forthe blood concentration of the active pharmaceutical ingredientfollowing administering a DSI pharmaceutical composition comprising thatactive pharmaceutical ingredient. As used herein the term “second Tmax”refers to the second relative maximum for the blood concentration of theactive pharmaceutical ingredient following administering a DSIpharmaceutical composition comprising that active pharmaceuticalingredient. The first Tmax occurs when a portion of the DSIpharmaceutical composition is absorbed via the non-keratinous fibers orin a mucosal cavity, for example in the mouth. The second Tmax then mayoccur as the remainder of the DSI pharmaceutical composition is absoebedviw the gastro-intestinal (GI) tract. In one embodiment, the first Tmaxis less than about 150 minutes. In another embodiment, the first Tmax isless than about 120 minutes. In another embodiment, the first Tmax isless than about 100 minutes. In another embodiment, the first Tmax isless than about 80 minutes. In another embodiment, the first Tmax isless than about 60 minutes. In another embodiment, the first Tmax isless than about 40 minutes. In one embodiment, the second Tmax is lessthan about 200 minutes. In another embodiment, the second Tmax is lessthan about 180 minutes. In another embodiment, the second Tmax is lessthan about 160 minutes. In another embodiment, the second Tmax is lessthan about 140 minutes. In another embodiment, the second Tmax is lessthan about 120 minutes. In another embodiment, the second Tmax is lessthan about 100 minutes.

In one embodiment, when the active pharmaceutical ingredient isomeprazole, one dose of a DSI pharmaceutical composition provides afirst Tmax and a second Tmax. In another embodiment, one dose of anomeprazole DSI pharmaceutical composition provides a first Tmax and asecond Tmax. In another embodiment, a dose of an omeprazole DSIpharmaceutical composition provides a first Tmax between about 30-60minutes and a second Tmax between about 120-160 minutes.

Disclosed herein are methods of controlling the production of digestivefluids, comprising administering an above-described the DSIpharmaceutical composition comprising omeprazole to an animal in need oftreatment. In one embodiment, the animal is an equine. In anotherembodiment, the animal is a human. In one embodiment, the methodcontrolling the production of digestive fluids comprises administeringto the said animal a first peak in blood omeprazole concentration and asecond peak in blood omeprazole concentration. In another embodiment,the administering a first peak in blood omeprazole concentration and asecond peak in blood omeprazole concentration are achieved byadministering one dose of omeprazole.

Disclosed herein are methods of treating or preventing gastric ulcers inan animal needing treatment, comprising administering an above-describedthe DSI pharmaceutical composition comprising omeprazole to an animal inneed of treatment. In one embodiment, the animal is an equine. Inanother embodiment, the animal is a human. In one embodiment, the methodof treating or preventing gastric ulcers in an animal needing treatmentcomprises administering to the said animal a first peak in bloodomeprazole concentration and a second peak in blood omeprazoleconcentration. In another embodiment, the administering a first peak inblood omeprazole concentration and a second peak in blood omeprazoleconcentration are achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing duodenal ulcersin an animal needing treatment, comprising administering anabove-described the DSI pharmaceutical composition comprising omeprazoleto an animal in need of treatment. In one embodiment, the animal is anequine. In another embodiment, the animal is a human. In one embodiment,the method of treating or preventing duodenal ulcers in an animalneeding treatment comprises administering to the said animal a firstpeak in blood omeprazole concentration and a second peak in bloodomeprazole concentration. In one embodiment, the administering a firstpeak in blood omeprazole concentration and a second peak in bloodomeprazole concentration are achieved by administering one dose ofomeprazole.

Disclosed herein are methods of treating or preventing Zollinger-Ellisonsyndrome in an animal needing treatment, comprising administering anabove-described the DSI pharmaceutical composition comprising omeprazoleto an animal in need of treatment. In one embodiment, the animal is anequine. In another embodiment, the animal is a human. In one embodiment,the method of treating or preventing Zollinger-Ellison syndrome ananimal needing treatment comprises administering to the said animal afirst peak in blood omeprazole concentration and a second peak in bloodomeprazole concentration. In one embodiment, the administering a firstpeak in blood omeprazole concentration and a second peak in bloodomeprazole concentration are achieved by administering one dose ofomeprazole.

Disclosed herein are methods of treating or preventing laryngopharyngealreflux in an animal needing treatment, comprising administering anabove-described the DSI pharmaceutical composition comprising omeprazoleto an animal in need of treatment. In one embodiment, the animal is anequine. In another embodiment, the animal is a human. In one embodiment,the method of treating or preventing laryngopharyngeal reflux in ananimal needing treatment comprises administering to the said animal afirst peak in blood omeprazole concentration and a second peak in bloodomeprazole concentration. In one embodiment, the administering a firstpeak in blood omeprazole concentration and a second peak in bloodomeprazole concentration are achieved by administering one dose ofomeprazole.

Disclosed herein are methods of treating or preventing dyspepsia in ananimal needing treatment, comprising administering an above-describedthe DSI pharmaceutical composition comprising omeprazole to an animal inneed of treatment. In one embodiment, the animal is an equine. Inanother embodiment, the animal is a human. In one embodiment, the methodof treating or preventing dyspepsia in an animal needing treatmentcomprises administering to the said animal a first peak in bloodomeprazole concentration and a second peak in blood omeprazoleconcentration. In one embodiment, the administering a first peak inblood omeprazole concentration and a second peak in blood omeprazoleconcentration are achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing peptic ulcerdisease in an animal needing treatment, comprising administering anabove-described the DSI pharmaceutical composition comprising omeprazoleto an animal in need of treatment. In one embodiment, the animal is anequine. In another embodiment, the animal is a human. In one embodiment,the method of treating or preventing peptic ulcer disease in an animalneeding treatment comprises administering to the said animal a firstpeak in blood omeprazole concentration and a second peak in bloodomeprazole concentration. In one embodiment, the administering a firstpeak in blood omeprazole concentration and a second peak in bloodomeprazole concentration is achieved by administering one dose ofomeprazole.

Disclosed herein are methods of treating or preventing gastritis in ananimal needing treatment, comprising administering an above-describedthe DSI pharmaceutical composition comprising omeprazole to an animal inneed of treatment. In one embodiment, the animal is an equine. Inanother embodiment, the animal is a human. In one embodiment, the methodof treating or preventing gastritis in an animal needing treatmentcomprises administering to the said animal a first peak in bloodomeprazole concentration and a second peak in blood omeprazoleconcentration. In one embodiment, the administering of a first peak inblood omeprazole concentration and a second peak in blood omeprazoleconcentration is achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing gastroesophagealreflux disease in an animal needing treatment, comprising administeringan above-described the DSI pharmaceutical composition comprisingomeprazole to an animal in need of treatment. In one embodiment, theanimal is an equine. In another embodiment, the animal is a human. Inone embodiment, the method of treating or preventing gastroesophagealreflux disease in an animal needing treatment comprises administering tothe said animal a first peak in blood omeprazole concentration and asecond peak in blood omeprazole concentration. In one embodiment, theadministering a first peak in blood omeprazole concentration and asecond peak in blood omeprazole concentration is achieved byadministering one dose of omeprazole.

Disclosed herein are methods of raising the pH in an animal's stomachcomprising administering an above-described DSI pharmaceuticalcomposition comprising omeprazole to the animal. In one embodiment, theanimal is an equine. In another embodiment, the animal is a human. Inone embodiment, the method of raising the pH of an animal's stomachcomprises administering to the said animal a first peak in bloodomeprazole concentration and a second peak in blood omeprazoleconcentration. In one embodiment, the animal is an equine. In anotherembodiment, the animal is a human. In one embodiment, the administeringa first peak in blood omeprazole concentration and a second peak inblood omeprazole concentration is achieved by administering one dose ofan omeprazole DSI pharmaceutical composition.

Disclosed herein are methods of making a DSI pharmaceutical compositioncomprising combining one or more active pharmaceutical ingredient(s)with one or more pharmaceutically inactive compound(s) to form apre-formulation, freezing the pre-formulation, reducing the pressuresurrounding the pre-formulation, and lyophilizing the pre-formulation.In one embodiment, the method comprises combining one or more activepharmaceutical ingredients with bovine gelatin and water to form apre-formulation, freezing the pre-formulation, reducing the pressuresurrounding the pre-formulation, and lyophilizing the pre-formulation toform a DSI pharmaceutical composition. In one embodiment, the methodcomprises combining one or more active pharmaceutical ingredients withbovine gelatin and water and also adding at least one compound chosenfrom mannitol, sucralose, a flavorant and a surfactant. In oneembodiment, the method comprises combining omeprazole with bovinegelatin, mannitol and water to form a pre-formulation, adjusting the pHof that formulation to a basic pH (e.g., between about 8 to 9, betweenabout 9 to 10, or between about 10 to 11 and preferably between about8-8.5, or 8.3), freezing the pre-formulation, then reducing the pressuresurrounding the pre-formulation and lyophilizing the pre-formulation toform a DSI pharmaceutical composition. The preformulation may alsooptionally contain a pharmaceutically acceptable surfactant, a flavorantand other additives and excipients known in the pharmaceutical andveterinary arts. The components of the pre-formulation may be dissolvedtogether in a single solution or prepared as separate solutions that arethen combined to make the pre-formulation.

In one embodiment, the pre-formulation comprises omeprazole, bovinegelatin, mannitol, and water in about the following relative proportionsby mass: 40:7:6:200, respectively. For example, an omeprazolepreformulation may contain about 1-10 mass % bovine gelatin, 1-10 mass %mannitol, about 0-0.5 mass % of a surfactant, about 0-0.2 mass % of aflavorant, about 10-30 mass % of omeprazole and about 45-90 mass %deionized (DI) water. A preferred preformulation contains about 3-5 mass% bovine gelatin, 3-5 mass % mannitol, about 0.1-0.3 mass % of asurfactant, about 0.05-0.15 mass % of a flavorant, about 15-25 mass % ofomeprazole and about 55-75 mass % DI water. The amount of omeprazole ina DSI pharmaceutical composition of the invention many range from about50 to 500 mg, preferably from about 100 to 300 mg, or be about 200 mg.In one embodiment, the DSI pharmaceutical composition produced by theabove method has a mass % of omeprazole of between about 65 mass %-about75 mass % omeprazole.

As mentioned above, pharmaceutically acceptable surfactants may beincluded in a DSI pharmaceutical composition of the invention. Exemplarysurfactants include, but are not limited to, sodium lauryl sulfate(SLS), sodium docusate and PEG. For DSI pharmaceutical compositions withomeprazole an anionic surfactant such as sodium docusate is generallypreferred. The surfactant aids in releasing the composition from abubble pack, e.g., preventing it from sticking to the package surface.Mixtures of surfactants may be used in a DSI pharmaceutical compositionof the invention.

Any flavorant used in pharmaceutical or veterinary formulations may beused. A mint flavor is one example. Fruit flavorants, such as citrus orcherry, are another example.

Advantageously, in at least some embodiments, DSI pharmaceuticalcompositions according to the disclosure may ensure complete andaccurate dosing with less stress for both the animal and the animalhandler. Further, the methods of the disclosure may allow for higherconcentrations of active ingredients, thereby minimizing the need formultiple dosing.

Effective amounts may vary according to various factors, such as, butnot limited to, the general health of the animal, the degree or severityof the particular disease under treatment, the age of the animal, theorgans infected or infested, and the like. In at least one embodiment ofthe therapeutic methods disclosed herein, the amount of the DSIpharmaceutical composition is sufficient to provide therapeutic levelsof the active ingredient as quickly as possible.

In one example, the active ingredient is omeprazole, the amount of saidDSI pharmaceutical composition administered is that sufficient toprovide about 0.5 mg/kg to about 8.0 mg/kg of active ingredient per bodyweight of the animal and about 1.0 mg/kg to about 6.0 mg/kg, about 4.0mg/kg of active ingredient per body weight of the animal, with anapproximate amount of about 5-700 mg omeprazole/dose, about 5-85 mgomeprazole/dose about 100-250 mg omeprazole/dose or about 350-550 mgomeprazole/dose, depending factors such as whether a low doseformulation or high dose formulation is needed and upon the animal beingtreated. For example, in humans omeprazole is administered in doses of5, 10, 20, and 40 mg.

In another embodiment, the method disclosed herein comprisesadministering less than about 100 mg of omeprazole to the animal perday. In some embodiments, the methods disclosed herein compriseadministering between about 1 mg to about 100 mg of omeprazole per dayor between about 10 mg to about 80 mg of omeprazole per day. In someembodiments, the methods disclosed herein comprise administering betweenabout 25 mg to about 75 mg of omeprazole per day.

In some embodiments, the methods and compositions of this disclosurecomprise controlling the pH of an animal's stomach. For example, thisdisclosure includes methods of controlling the pH of an animal's stomachcomprising administering omeprazole to an animal. As used herein theterm controlling means maintaining a pH range that is healthy for theanimal; maintaining does not necessarily include raising or lowering thepH to achieve the said healthy pH range.

In a further exemplary embodiment, the active ingredient is omeprazoleand the amount of the DSI pharmaceutical composition administered isthat sufficient to provide omeprazole at a pH of greater than about 6.In other exemplary embodiments, omeprazole is administered to theanimal's non-keratinous fibers at a pH of about 10.

Animals suitable for treatment in the disclosed methods includehomeothermic animals, for example, humans, equine, bovine, ovine,porcine, caprine, canine, feline or the like animals. For example, thedisclosed methods would provide a benefit to any animal for whom themetabolic disposition of an active pharmaceutical ingredient is foundproblematic, or for which initial dose titration may pose risks, orwhich is otherwise undesirable.

The above disclosed doses and dosage ranges are not intended to belimiting. A practitioner skilled in the art may likewise administersuitable DSI pharmaceutical compositions (e.g., immediate or rapidrelease formulation) in single or divided doses, according to thedesired therapeutic effect. Thus, in certain clinical situations it maybe desirable to administer compositions to give initial high levels ofthe active ingredient, followed by lower dose maintenance doses.

EXAMPLES

The preparation and characterization of DSI pharmaceutical compositionsof the invention are described below. The DSI pharmaceuticalcompositions described below were characterized using the followingtests:

Dry Weight—

Weights of ten units were measured individually using an analyticalbalance to determine consistency of unit dosage.

Disintegration Time—

This test determined the speed of which a DSI unit disintegrate in watermaintained at 37.0° C.±0.5° C. Testing is carried out using a USPDisintegration Tester and a calibrated thermometer and timer.

Load to Fracture—

This test was used to determine the force in Kg at which a DSI unit willbreak using TA-XT2 Texture Analyser 3-point bend test.

Appearance—

The test evaluates the physical appearance of top and bottom surface ofDSI units particularly relating to freeze drying defects such asmelting, shrinkage of unit and cracking. Rating from 1 (the worst) to 10(the best) are assigned after examination of 10 units.

Assay—

To determine the % LC, testing was performed using Agilent 1100 and 1200HPLC systems connected to a TotalChrom acquisition system for datacollection and processing.

Example 1: DSI Pharmaceutical Composition of Omeprazole

DSI pharmaceutical compositions of the invention were prepared usingomeprazole as the active pharmaceutical ingredient (API). Theingredients used to manufacture the DSI pharmaceutical compositions arelisted in Table 1. Omeprazole was sourced from Srini PharmaceuticalsLimited, India, and all other materials were supplied by CatalentPharmaceutical Solutions, LLC.

TABLE 1 List of Ingredients Ingredient Function Specification OmeprazoleAPI Bovine Gelatin Matrix former USP Mannitol Bulking agent USP DocusateSodium Surfactant/Wetting Agent USP Mint Flavor Flavor Non-compendiaPurified Water Vehicle USP (deionized water, DI water) Sodium HydroxidepH adjustment ACS grade

The DSI pharmaceutical composition was manufactured using the processdescribed below. A 200 mg omeprazole DSI pharmaceutical composition wasprepared. Table 2 lists the amount of each ingredient used.

Manufacturing Procedure:

-   -   1. Purified water was transferred to an appropriate sized beaker        and heated to 60° C.±5° C.    -   2. Gelatin and mannitol were then added and mixed with a        magnetic stir bar until completely dissolved to form a first        solution.    -   3. The first solution was then cooled to about 30° C.    -   4. Purified water was transferred to a second beaker and heated        to 45° C.±5° C. to allow the docusate sodium surfactant to        rapidly dissolve when added.    -   5. Docusate Sodium was then added and mixed with a magnetic stir        bar until completely dissolved to form a second solution.    -   6. The second solution was then cooled to room temperature (25°        C.).    -   7. Omeprazole, as the API, was added to the second solution        (prepared in step 5) and stirred for 1 hour.    -   8. Slowly added the first solution of gelatin and mannitol mix        to the second solution of API mix and stirred for 1 hour.    -   9. If needed, sweetener and/or flavors were then added and        stirred to mix for about 30 minutes.    -   10. pH adjustments to about 8.3±0.2 using Sodium Hydroxide.    -   11. Q.S. to final weight using purified water.    -   12. The solution/suspensions were stirred for at least 60        minutes prior to dispensing.    -   13. Dispensing was performed using an IVEK Dispenses 700 pump.        Weight checks were performed initially at the set up stage as        well as intermittently during dosing.    -   14. The solutions were dispensed into preformed blister trays        having pocket sizes prepared using a Rohrer R550 tray former to        hold 1000 mg of the solution.    -   15. The filled blister trays were frozen using an Air Products        cryogenic freezer.    -   16. The frozen blisters were stored at a −30° C. set-point in a        Revco freezer until used in freeze drying.    -   17. The frozen units were freeze dried at −15° C. (unless        otherwise indicated) using a FTS Lyostar-II freeze dryer having        three shelves.    -   18. The freeze dried units were handled in a low humidity        manufacturing area and were sealed in Marvelseal 360 sachets        using a Traco sealer.

TABLE 2 200 mg Omeprazole DSI Pharmaceutical Composition Ingredient WetMass % Wet Mass/Unit Dry Mass % Bovine gelatin 3.5%  35 mg 13% Mannitol3.0%  30 mg 11% Sodium Docusate 0.2%  2 mg 0.7%  Mint Flavor 0.1%  1 mg0.4%  Omeprazole 20.0%  200 mg 75% Purified (DI) Water 73.2%  732 mg —Total 100%  1000 mg 

Batches of DSI pharmaceutical compositions containing 200 mg ofomeprazole using the manufacturing process above with the batchvariations described in Table 3. Units from each batch werecharacterized by Appearance, Load to Fracture and Disintegration Time.The results are reported in Tables 4-6, respectively.

TABLE 3 Batch Variations Batch Number Batch Variations 1-1 0.1%Surfactant Freeze dried at 0.0° C. shelf temperature 1-2 0.1% SurfactantFreeze dried at 15.0° C. shelf temperature 1-3 0.1% Surfactant Freezedried at −15.0° C. shelf temperature 1-4 0.1% Surfactant Freeze driedfor 4 hours 1-5 0.1% Surfactant Freeze dried for 6 hours 1-6 0.1%Surfactant Freeze dried for 8 hours

TABLE 4 Appearance Testing Results Batch Number Rating AppearanceDescription 1-1 6 White round tables with some collapse at the top andpitted marks with units sticking to foil 1-2 6 White round tables withsome collapse at the top and pitted marks with units sticking to foil1-3 7 White round tables with some collapse at the top 1-4 6 White roundtables with some collapse at the top and minor cracking with unitssticking to foil 1-5 6 White round tables with some collapse at the topand minor cracking with units sticking to foil 1-6 6 White round tableswith some collapse at the top with units sticking to foil

TABLE 5 Load to Fracture Results (Kg) Batch Number Unit # 1-1 1-2 1-31-4 1-5 1-6 1 0.565 0.801 0.685 0.754 0.889 0.640 2 0.638 0.708 0.7790.655 0.759 0.837 3 0.566 0.753 0.639 0.580 0.893 0.656 4 0.595 0.7270.778 0.678 0.837 0.717 5 0.544 0.907 0.907 0.659 0.898 0.766 Avg. 0.5820.779 0.758 0.665 0.855 0.723

TABLE 6 Disintegration Time (seconds) Batch Number Unit # 1-1 1-2 1-31-4 1-5 1-6 1 2 8 2 3 3 2 2 3 10 2 2 3 2 3 2 11 3 2 2 3 4 2 13 2 3 3 2 53 11 2 2 2 2 Max Time 3 13 3 3 3 3

Example 2: Formulation Design of Experiments for DSI PharmaceuticalCompositions of Omeprazole

A Design of Experiments (DOE) study was performed by manufacturing andtesting nine batches on a 250 gram wet mass scale. The DOE study, usinga 2 level, 3 factor design (8 experiments), varied three parameters: theamount of bovine gelatin, the amount of mannitol and the shelftemperature. A centerpoint experiment was added to the design for atotal of 9 experiments. Table 7 describes the DOE study parameters interms of the wet mass percent of bovine gelatin and mannitol and dryingtemperature.

TABLE 7 DOE Study Parameters (wet mass %) Factor 1 Factor 2 Factor 3Experiment (Gelatin) (Mannitol) (Drying Temp) 2-6 4.5% 2% −15° C. 2-14.5% 2% +15° C. 2-4 4.5% 4% −15° C. 2-9 4.5% 4% +15° C. 2-2 2.5% 2% −15°C. 2-3 2.5% 2 +15° C. 2-7 2.5% 4% −15° C. 2-5 2.5% 4% +15° C. 2-8 3.5%3%  0° C.

The manufacturing process of Example 1 was used with the followingprocess parameters: (i) the freezing step was at −50° C. setpoint with a3.3 minute cycle; (ii) in the freeze-drying, the unit loading was at−25° C. with a ramp rate of 1.5-2° C./min to reach primary dryingset-point/375 mTorr; (iii) the primary drying was at −15° C., 0° C. or15° C. shelf-temperature (these are the Low-Mid-High variables for theDOE) using constant vacuum of 375 mTorr and a time of 6 hours; and (iv)the secondary drying was at a ramp rate of 1.5-2° C./min to 22° C. TheDOE outputs were three sets of physical data: Appearance (Table 8), Loadto Fracture (Table 9) and Disintegration Time (Table 10).

The center-point batch (Experiment 8) yielded optimal physical data,with an Appearance rating of 10/10 and 3 second disintegration time. TheDOE study did not yield data supporting a formulation change from thecenter-point batch. However, data analysis using Minitab® software(version 16.21) did identify a number of significant interactions. Asingle value of “Desirability” was determined based on the study outputswhich are displayed on FIG. 1 (fixed shelf temp. of 15° C.), FIG. 2(fixed shelf temp. of 0° C.) and FIG. 3 (fixed shelf temp. of −15° C.).This DOE study did show that (i) overall, changes in gelatinconcentration have a much greater affect on desirability of the DISpharmaceutical composition of omeprazole than changes in mannitolconcentration; and (ii) low level freeze drying (shelf) temperature ismost favorable, yielding the best desirability scores and also anapparent robust knowledge space at the centerpoint.

TABLE 8 DOE Appearance Testing Results Batch # Rating AppearanceDescription 2-6 6 White round tablets with some base melting and pittedunits 2-1 3 White round tablets with a hollow layer above the base 2-4 4White round tablets with significant base melting in almost all units2-9 3 White round tablets with a hollow layer above the base 2-2 4 Whiteround tablets that are very fragile and with cracks traversing the widthof the tablets 2-3 6 White round tablets with some minor cracks andsticking to foil 2-7 9 White round tablets with rough surface but noother defects 2-5 7 White round tablets with some very minor cracks andsticking to foil 2-8 10 White round tablets free of defects

TABLE 9 DOE Load to Fracture Results (Kg) Batch Number Unit # 2-6 2-12-4 2-9 2-2 2-3 2-7 2-5 2-8 1 1.490 1.065 1.920 1.680 0.196 0.170 0.2880.236 0.804 2 1.691 1.288 2.372 1.213 0.164 0.136 0.252 0.278 0.960 31.789 1.139 1.789 1.223 0.050 0.164 0.269 0.236 0.821 4 1.881 1.2291.915 1.225 0.122 0.167 0.248 0.280 0.795 5 2.050 1.260 2.250 1.2910.114 0.167 0.306 0.330 0.739 Avg. 1.780 1.196 2.049 1.326 0.129 0.1610.273 0.272 0.824

TABLE 10 DOE Disintegration Testing Results (min:sec) ExperimentalNumber Unit # 2-6 2-1 2-4 2-9 2-2 2-3 2-7 2-5 2-8 1 0:05 0:31 1:28 0:261:55 0:02 0:01 0:05 0:03 2 0:05 0:27 1:31 0:23 1:12 0:01 0:02 0:04 0:033 0:05 0:31 1:27 0:22 1:28 0:02 0:02 0:05 0:03 Max 0:05 0:31 1:31 0:261:55 0:02 0:02 0:05 0:03 Time

Example 3: Stability Studies of DSI Pharmaceutical Compositions ofOmeprazole

Two batches of DSI pharmaceutical compositions of omeprazole, 200 mgunit, were manufactured using the method of Example 1 but at differentpH of 7.96 and 8.47. The tablets were packaged in Marvel Seal 360aluminum sachets with 4 trays of 8 tablets each (32 tablets). The DSIpharmaceutical compositions were placed on accelerated conditions togenerate stability data. As is known in the art, omeprazole undercertain aqueous conditions is chemically unstable. The DSIpharmaceutical compositions were stored at 25° C./60% RH and 40° C./75%RH storage conditions and tested on an initial (T=0), one month (T=1)and three month (T=3) time points. The testing included contentuniformity (at initial time point (T=0) only) in compliance with USP<905>, Appearance, Assay, Disintegration and Load-to-fracture. The datafor each batch 3-1 and 3-2 is reported in Tables 10, 11 and 12,respectively.

TABLE 10 Initial (T = 0) Content Uniformity Batch 3-1 Batch 3-2 % %Sample Content Sample Content 1 99.3 1 100.3 2 99.4 2 100.4 3 99.3 399.9 4 99.2 4 99.9 5 99.3 5 100.3 6 99.1 6 100.3 7 98.9 7 100.4 8 99.2 8100.5 9 98.9 9 100.4 10  98.3 10  100.8 Average 99.1 Average 100.3 Std.Dev. (SD) 0.3 Std. Dev. (SD) 0.3 % Rel. Std. 0.3 % Rel. Std. 0.3 Dev. (%RSD) Dev. (% RSD) Acceptance 0.8 Acceptance 0.6 Value (AV) ≤L1% Value(AV) ≤L1% (L1 = 15.0) (L1 = 15.0)

TABLE 11 Stability Test Results, Batch 3-1 Initial (T = 0) 1 Month (T= 1) 3 Month (T = 3) Sample 25° C./60% 40° C./75% 25° C./60% 40° C./75%25° C./60% 40° C./75% Test # RH RH RH RH RH RH Appearance White, White,White, White, White, White, round round round round round round tabletstablets tablets tablets tablets tablets Assay 1 99.2% LC 99.2% LC 98.8%LC 98.8% LC 99.6% LC 99.6% LC 2 99.4% LC 99.4% LC 98.5% LC 98.9% LC100.8% LC 99.8% LC Average 99.3% LC 99.3% LC 98.7% LC 98.8% LC 100.2% LC99.7% LC Disintegration 1 5 sec 5 sec  7 sec 9 sec 11 sec 11 sec Time 26 sec 6 sec 10 sec 8 sec 11 sec 10 sec 3 7 sec 7 sec  7 sec 9 sec 10 sec 9 sec 4 6 sec 6 sec 11 sec 9 sec 11 sec 11 sec 5 5 sec 5 sec  7 sec 8sec  9 sec 12 sec 6 — — 12 sec 9 sec 11 sec 11 sec Max 7 sec 7 sec 12sec 9 sec 11 sec 12 sec Load to 1 0.800 Kg 0.800 Kg 0.705 Kg 0.906 Kg0.758 Kg 0.854 Kg Fracture 2 0.910 Kg 0.910 Kg 0.740 Kg 0.804 Kg 0.833Kg 0.864 Kg 3 0.795 Kg 0.795 Kg 0.814 Kg 0.758 Kg 0.811 Kg 0.785 Kg 40.690 Kg 0.690 Kg 0.696 Kg 0.967 Kg 0.695 Kg 0.833 Kg 5 1.215 Kg 1.215Kg 0.593 Kg 0.800 Kg 0.901 Kg 0.999 Kg Average 0.882 Kg 0.710 Kg 0.847Kg 0.800 0.867 Kg

TABLE 12 Stability Test Results, Batch 3-2 Initial (T = 0) 1 Month (T= 1) 3 Month (T = 3) Sample 25° C./60% 40° C./75% 25° C./60% 40° C./75%25° C./60% 40° C./75% Test # RH RH RH RH RH RH Appearance White, White,White, White, White, White, round round round round round round tabletstablets tablets tablets tablets tablets Assay 1 100.1% LC 100.1% LC99.4% LC 99.4% LC 100.5% LC 100.5% LC 2 100.1% LC 100.1% LC 99.6% LC99.8% LC 100.5% LC 100.8% LC Average 100.1% LC 100.1% LC 99.5% LC 99.6%LC 100.5% LC 100.7% LC Disintegration 1 4 sec 4 sec 9 sec 6sec 11 sec 9sec Time 2 6 sec 6 sec 9 sec 6 sec 10 sec 8 sec 3 6 sec 6 sec 8 sec 8sec  7 sec 7 sec 4 6 sec 6 sec 9 sec 8 sec  9 sec 8 sec 5 4 sec 4 sec 8sec 6 sec 10 sec 8 sec 6 — — 8 sec 7 sec  8 sec 7 sec Max 6 sec 6 sec 9sec 8 sec 11 sec 9 sec Load to 1 0.667 Kg 0.667 Kg 0.975 Kg 0.606 Kg0.800 Kg 0.651 Kg Fracture 2 0.840 Kg 0.840 Kg 0.792 Kg 0.620 Kg 0.833Kg 0.743 Kg 3 0.799 Kg 0.799 Kg 0.953 Kg 0.982 Kg 0.899 Kg 0.890 Kg 41.097 Kg 1.097 Kg 0.574 Kg 0.623 Kg 0.667 Kg 0.880 Kg 5 0.737 Kg 0.737Kg 0.886 Kg 0.657 Kg 0.754 Kg 0.701 Kg Average 0.828 Kg 0.828 Kg 0.836Kg 0.698 Kg 0.791 Kg 0.773 Kg

In the compositions and methods described herein, where a particularcompound is recited, applicants contemplate isolated enantiomers andmixtures thereof in any proportions. For example, where the only onestereoisomer is stated for a particular stereocenter, applicantscontemplate any possible stereoisomer at that position. For example,where the compound omeprazole is used, it should be understood thatapplicants contemplate either pure isomer and/or any mixture thereof.

It is to be understood that the foregoing description is exemplary andexplanatory only, and not to be interpreted as restrictive of thedisclosure.

Various modifications of this disclosure, in addition to those shown anddescribed herein, will become apparent to those skilled in the art fromthe following examples and the foregoing description. Such modificationsare also intended to fall within the scope of the present disclosure.Other embodiments will be apparent to those skilled in the art fromconsideration of the disclosure and practice of the various exemplaryembodiments disclosed herein.

It is also to be understood that, as used herein the terms “the,” “a,”or “an,” mean “at least one,” and should not be limited to “only one”unless explicitly indicated to the contrary. Thus, for example, the useof “a pharmaceutically active ingredient” or “a therapeutic agent” isintended to mean at least one therapeutic agent. Unless otherwiseindicated, all numbers or ranges used in the specification and claimsare to be understood as being modified in all instances by the term“about,” whether or not so stated. It should also be understood that theprecise numerical values used in the specification and claims formadditional embodiments of the disclosure, and are intended to includeany ranges which can be narrowed to any two end points disclosed withinthe exemplary ranges and values provided. Efforts have been made toensure the accuracy of the numerical values disclosed herein. Anymeasured numerical value, however, can inherently contain certain errorsresulting from the standard deviation found in its respective measuringtechnique.

The claimed invention is:
 1. A method of making a pharmaceuticalcomposition for direct system introduction, the composition comprising:about 10-17 dry mass % bovine gelatin, about 10-17 dry mass % mannitol,about 0-1 dry mass % of a surfactant, about 0-0.5 dry mass % of aflavorant, and about 65-80 dry mass % of an active pharmaceuticalingredient which is a proton pump inhibitor; wherein the methodcomprises: combining the active pharmaceutical ingredient with one ormore pharmacologically inactive compound(s) to form a pre-formulation;freezing the pre-formulation; reducing the pressure surrounding thepre-formulation; and lyophilizing the pre-formulation.
 2. The methodaccording to claim 1, wherein the method comprises combining thepharmaceutically active ingredient with bovine gelatin and water andadding at least one compound selected from mannitol, flavorant, andsurfactant.
 3. The method according to claim 1, wherein the methodfurther comprises adjusting the pH of the pre-formulation.
 4. The methodaccording to claim 1, wherein the method further comprises adjusting thepH of the pre-formulation to a basic pH value.
 5. The method accordingto claim 4, wherein the pH is adjusted to between about 8 to 9; betweenabout 9 to 10; between about 10 to 11; between about 8 to 8.5; or about8.3.
 6. The method according to claim 1, wherein the pre-formulationcomprises the surfactant, flavorant, and/or other excipients.
 7. Themethod according to claim 1, wherein the components of thepre-formulation are dissolved together in a single solution.
 8. Themethod according to claim 1, wherein the components of thepre-formulation are prepared as separate solutions that are combined tomake the pre-formulation.
 9. The method according to claim 1, whereinthe pre-formulation comprises: about 1-10 mass % bovine gelatin; about1-10 mass % mannitol; about 0-0.5 mass % surfactant; about 0-0.2 mass %flavorant; about 10-30 mass % of the proton pump inhibitor; and about45-90 mass % water.
 10. The method according to claim 1, wherein thepre-formulation comprises: about 3-5 mass % bovine gelatin; about 3-5mass % mannitol; about 0.1-0.3 mass % surfactant; about 0.05-0.15 mass %flavorant; about 15-25 mass % of the pharmaceutically active ingredient;and about 55-75 mass % water.
 11. The method according to claim 1,wherein the pharmaceutical composition comprises: about 10-17 dry mass %bovine gelatin, about 10-17 dry mass % mannitol, and about 0-0.5 drymass % of a surfactant.
 12. The method according to claim 1, wherein thepharmaceutical composition comprises: about 10-13 dry mass % bovinegelatin, about 12-15 dry mass % mannitol, and about 0.1-0.3 dry mass %of a surfactant.
 13. The method according to claim 1, wherein the activepharmaceutical ingredient is omeprazole or esomeprazole.
 14. The methodaccording to claim 1, wherein the pharmaceutical composition has adisintegration time of 7 seconds or less in deionized water maintainedat 37.0° C.±0.5° C.
 15. The method according to claim 1, wherein thepharmaceutical composition has a disintegration time of 4 seconds orless in deionized water maintained at 37.0° C.±0.5° C.
 16. A method ofdelivering an active pharmaceutical ingredient which is a proton pumpinhibitor to an animal via the animal's non-keratinous tissuescomprising the step of placing the pharmaceutical composition preparedaccording to claim 1 into a mucosal cavity of an animal to be treatedwith the active pharmaceutical ingredient.
 17. The method according toclaim 16, wherein the animal is equine.
 18. The method according toclaim 16, wherein the animal is human.
 19. The method according to claim16, wherein the mucosal cavity is selected from an oral cavity, an analcavity, a vaginal cavity, a nasal cavity, a gingival mucosa, a lingualmucosa, a palatal mucosa, a pharyngeal mucosa, a sublingual mucosa, anda non-gastric mucosa.
 20. The method according to claim 16, wherein theactive pharmaceutical ingredient is omeprazole or esomeprazole.
 21. Themethod according to claim 16, wherein the mucosal cavity is an oralcavity.
 22. A method of treating a disease selected from the groupconsisting of gastric ulcers, duodenal ulcers, Zollinger-Ellisonsyndrome, laryngopharyngeal reflux, dyspepsia, peptic ulcer disease,gastritis, and gastroesophageal reflux in an animal, the methodcomprising administering an effective amount of the pharmaceuticalcomposition prepared according to claim 1 to the animal.
 23. The methodaccording to claim 22, wherein administering comprises placing thepharmaceutical composition into a mucosal cavity of the animal.
 24. Themethod according to claim 23, wherein the mucosal cavity is selectedfrom an oral cavity, an anal cavity, a vaginal cavity, a nasal cavity, agingival mucosa, a lingual mucosa, a palatal mucosa, a pharyngealmucosa, a sublingual mucosa, and a non-gastric mucosa.
 25. The methodaccording to claim 22, wherein the animal is equine.
 26. The methodaccording to claim 22, wherein the animal is human.